Abstract P108: Genome-wide Association Study of Activated Partial Thromboplastin Time in Multi-Ethnic Populations

Abstract

Background: Activated partial thromboplastin time (aPTT) is a clinical test used to measure the clotting time between the activation of factor XII and the formation of a fibrin clot. Prolonged aPTT indicates a deficiency in the coagulation pathway while shortened aPTT is associated with prothrombotic risk factors and venus thromboembolism. Despite the high heritability of aPTT (40-80%), previous genome-wide association studies (GWAS) of aPTT have been limited to European descent populations, with only a smaller candidate gene study conducted in African Americans. Methods: We included 13,803 participants of European ancestry (EU) and 2,724 participants of African American ancestry (AA) from the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. aPTT, in seconds (s), was measured using standard protocols in plasma with the use of automated coagulometers. Genotype data were imputed to the 1000 Genomes Phase 1 reference panel, and associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry, age, sex, and study design. Study-specific results were combined using a fixed-effects, inverse variance weighted meta-analysis. Results: We identified seven loci associated with aPTT in EU populations ( F5, FRMD5, KNG1, F11, F12, HLA, ABO ) and three loci associated with aPTT in AA populations ( KNG1, F12, ABO ) at genome-wide significant levels ( P < 5x10 -8 ). These results are consistent with previously reported genetic studies in EU and AA populations. Effect sizes were larger in AA populations (1.08 to 1.32 s) than in EU populations (0.40 to 1.00 s). Conclusions: We successfully replicated associations with aPTT at seven loci in EU populations and three loci in AA populations. Our results suggest that genetic determinants of aPTT are consistent across race/ethnicity but that studies in AA populations are currently underpowered relative to EU populations. Future work in aPTT genetics should consider more diverse populations.